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Study of antibiotic tolerance paves the way for new treatments

ITHACA, New York – A new study has identified a mechanism that makes bacteria tolerate penicillins and related antibiotics, findings that could lead to new therapies that enhance the effectiveness of these treatments.

Antibiotic tolerance is the ability of bacteria to survive antibiotic exposure, in contrast to antibiotic resistance, when bacteria are already growing in the presence of antibiotics. Tolerant bacteria can lead to an infection that persists after treatment and may develop resistance over time.

The study in mice titled “The Multifaceted Cellular Damage Repair Path and Prevention Pathway Promotes High-Level Tolerance to Beta-Lactam Antibiotics”, published February 3 in the journal. EMBO Reports, Reveals how tolerance occurred, thanks to a system that reduces iron toxicity in bacteria that have been exposed to penicillin.

“We hope we can design a drug or develop antibiotics that help kill these fundamentally tolerant cells,” said lead author Tobias Dor, associate professor of microbiology at the Weill Institute of Cellular and Molecular Biology at the College of Agriculture. Life science.

Co-authors include Ilana Brito, a researcher at Mong Family Sesquicentennial College and assistant professor at the Meinig School of Biomedical Engineering at the School of Engineering, and Lars Westblade, associate professor of pathology and laboratory medicine at Weill Cornell Medicine.

Some bacteria, including the model bacteria used in the study, Vibrio cholerae, that cause cholera in humans, are significantly tolerant of penicillin and related antibiotics, known as beta-lactam antibiotics. It has long been known that beta-lactam antibiotics break down bacterial cell walls, but how bacteria survive the loss of their cell walls was not well understood.

In the study, researchers developed a Vibrio cholerae mutation that lacks two components of a damage-repair response system that controls a gene network that encodes various functions. Without the system, known as VxrAB, when the cell wall is damaged by antibiotics, the transport of electrons across the cell membrane is skewed, eventually leading to the electrons on the wrong molecules. This wrong direction causes a build-up of hydrogen peroxide in the cell, which alters the cell’s iron oxidation state and disrupts signals for the cell to see how much iron is in it.

In the presence of hydrogen peroxide, the mutant bacteria are unable to sense the amount of iron obtained, and behave as if they are iron-hungry and seek more iron. If left unchecked, these conditions cause iron poisoning that will kill the cell, according to experiments conducted by researchers. In other tests with Vibrio cholerae, both in test tubes and in mice, the researchers showed that reducing iron influx increases the bacteria’s tolerance to beta-lactam.

Fortunately for Vibrio cholerae, exposure to antibiotics and breakdown of cell walls activates the VxrAB system, which repairs cell walls and reduces iron absorption systems, thus creating antibiotic tolerance. More study is needed to understand what triggers the VxrAB regimen in the presence of beta-lactam antibiotics.

Research opens the door to developing new drugs that can be combined with antibiotics to exploit oxidative damage and iron flux in resistant bacteria. In future work, researchers will look for parallel mechanisms of tolerance to other bacterial pathogens.

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Jung-Ho Shin, a postdoctoral researcher in Dörr’s lab, is the first author of this paper. The co-authors are researchers from the Korea Advanced Institute of Science and Technology, the Korea Advanced Institute of Science and Technology, and the Intelligent Synthetic Biology Center in Korea.

The study was funded by the National Research Foundation of Korea and the National Institutes of Health.

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